Lung cancer is the most common cause of cancer death for women and men. Given this, there is a pressing need to improve lung cancer prevention and treatment. This is the subject of this competing renewal of NIH R01-CA087546-10 that takes advantage of a previously unrecognized chemoprevention pathway uncovered during the prior funding period. This is constituted by the E1- like ubiquitin-activating enzyme (UBE1L), which partners with the ubiquitin-related interferon stimulated gene 15 (ISG15) that can destabilize cyclin D1 and other complexed proteins. The consequence is G1 checkpoint arrest that permits repair of carcinogenic DNA damage. Notably, the specific UBE1L-ISG15 deconjugase UBP43/USP18 is a key regulator of this pathway. We propose this as target for chemoprevention and hypothesize that targeting UPB43 destabilizes cyclin D1 and other ISG15 complexed proteins. This confers therapeutic and chemopreventive effects in the lung. This hypothesis will be pursued through these Specific Aims: (1) to learn whether UBP43 is a key regulator of the G1-S transition; (2) to establish whether UBP43 knock-down represses lung cancer growth, tumorigenicity, or affects response to chemotherapy and chemoprevention agents; and (3) to validate the biological and clinical relevance of this pathway using novel transgenic mouse models that we engineered to mimic key features of clinical lung cancer. We will cross these mice with those that have lung-specific loss of UBP43 and interrogate a paired normal-malignant lung tissue bank and a lung cancer tissue array that permits clinical associations. Intriguingly, our proof of principle trial platform at Dartmouth found this pathway is engaged in lung cancers of patients treated with the rexinoid bexarotene, a candidate chemopreventive agent. Unique cellular, biochemical, experimental and clinically-predictive transgenic mouse models as well as paired normal-malignant lung tissue banks will be used by our highly collaborative and interdisciplinary team. Successful completion of this proposal should have substantial translational impact. This would uncover a novel pharmacologic target to combat lung cancer, a major cancer problem that we must confront.